INTERFERON GAMMA DRASTICALLY MODIFIES THE REGULATION OF INTERLEUKIN-1 GENES BY ENDOTOXIN IN U937 CELLS

IL-1α, IL-1β, and tumor necrosis factor α (TNF-α) gene expression is induced by LPS (endotoxin) in monocytes/macrophages and in some monocytic cell lines. IFNγ and 1α,25-dihydrovitamin D3 (1,25[OH]2D3) are important macrophage-activating factors. They induced changes in the human monocyte cell line U937 that reflect cellular differentiation. We have studied the effect of IFN-γ and of 1,25(OH)2D3 on the expression of IL-1 and TNF-α messenger RNA in response to LPS. The induction of these genes by LPS is immediate and transient, with a maximum in 3 h. Preincubation of the cells with IFN-γ or with 1,25(OH)2D3 increases these mRNA responses to LPS about fourfold. More importantly, cells exposed to IFN-γ for 72 h exhibit a drastically different and unexpected pattern of IL-1α and IL-1β gene response to LPS. Instead of the normal transient response, one then observes a sustained increase in IL-1α and IL-1β gene expression over at least 16 h after LPS stimulation. This was measured both at the level of mRNA and by direct transcription assays (run-off). This striking effect of INF-γ on the kinetics of IL-1 gene response does not apply to the TNF-α gene. Interestingly, 1,25(OH)2D3, which shares with IFN-γ a number of important effects on monocytes/macrophages, does not affect the kinetics of IL-1 gene response to LPS. In view of the biological relevance of endotoxin as a macrophage activator, the potential clinical implication of this prolonged induction of IL-1 gene expression is discussed.